The Immune System: The Art of Fighting

The immune system is often described as a defensive army that hunts only harmful invaders, but its true function is far more nuanced. The essence of this system is the intelligent development of tolerance towards the body's own tissues and harmless foreign bodies. In other words, the immune system's success lies not only in its offensive power but also in its skillful avoidance of unnecessary or harmful responses. Therefore, immune tolerance maintains physiological balance by preventing unnecessary alarm in the face of the organism's own cells and harmless environmental stimuli. The primary cells that maintain this delicate balance are regulatory T cells (Tregs), the biological architects of tolerance. Treg cells contribute to maintaining immune homeostasis by suppressing excessive immune responses to autoantigens and the gut microbiota. Thus, the immune system is not merely an aggressive line of defense but rather a master of selective and sustained responses, protecting the body's integrity.

What is Immune Tolerance?

Immune tolerance is the immune system's mastery of distinguishing between "self" and "foreign." When this balance is disrupted, the system targets friend rather than foe, resulting in autoimmune diseases like lupus, type 1 diabetes, and rheumatoid arthritis. In other words, immune tolerance is not merely passive silence but the body's peace diplomacy.

Recent research has shown that regulatory T cells are not limited to their role in preventing autoimmune diseases but can also harm immune system function. A study published in Nature Reviews Immunology (2024) demonstrates that Treg cells benefit by suppressing autoimmune responses but also allow cancer cells to protect themselves from the immune system by inhibiting the immune response in the tumor microenvironment. These findings highlight complex ethical and biological challenges in the development of Treg-targeted therapies; in particular, the question of how to achieve the optimal balance between defense and harm is paramount.

Cell Metabolism (2025) emphasizes that Treg function is not solely under genetic control; cellular metabolism is also a determining factor. Fatty acid oxidation and mitochondrial energy production are directly related to the suppressive capacity of Tregs. When energy balance is disrupted, the immune system can attack its own tissues.

Finally, a study in Science Immunology (2024) shows that the gut microbiota is an ecosystem that “educates” Tregs. Specifically, short-chain fatty acids promote immune tolerance by stimulating Treg differentiation.

All these findings suggest that the immune system is a complex network operating not between black and white, but in countless shades of gray. How active or suppressed Tregs are depends not only on our genes but also on our dietary habits, microbiota, and cellular energy flow.

Guardians of Peace

One of the most important players in immune tolerance is the regulatory T cells (Treg) . These cells keep inflammation under control by suppressing the immune system's overreactions. They are recognized by a transcription factor called FoxP3, effectively their "identity card."

Without Tregs, the immune system quickly self-destructs. Deletion of the FoxP3 gene in mice causes fatal autoimmune syndromes. In humans, mutations in this gene cause a severe immune disorder known as IPEX syndrome . Therefore, Tregs are not only regulatory cells but also essential for life .

However, recent research has shown that Tregs are not always "good." Articles in Nature Reviews Immunology (2024) and Cell Metabolism (2025) have revealed that Treg cells can switch roles depending on the environment . While their suppressive power is insufficient in autoimmune diseases, they can become overactive in cancer tissues, protecting tumors. Treg accumulation in the tumor microenvironment prevents immune cells from attacking cancer cells. Therefore, many current cancer immunotherapies target Treg activity. However, there is a paradoxical subtlety here: if Tregs are overactive, defenses are weakened; if they are insufficient, autoimmunity develops. In other words, the immune system maintains a "balance of life and death" on a microscopic scale. It's not just genetic signals that determine Treg cell behavior; energy metabolism also plays a critical role. Tregs derive their energy largely from fatty acid oxidation and mitochondrial function . When this system is disrupted, they lose their cell-suppressive properties, and inflammation increases. Cell Metabolism (2025) describes this connection with the concept of “metabolic immunity”: The immune balance extends to the energy source of the cells.

Gut Microbiota: The Secret Ally

Immune tolerance is shaped not only by immune cells but also by the gut microbiota. A Science Immunology (2024) study shows that short-chain fatty acids produced by certain bacteria activate Treg cells. In other words, the microbiota sends a "calm down" message to the immune system. When this relationship is disrupted, for example, by antibiotic use or poor nutrition, tolerance can be broken. Our gut essentially functions as the immune system's diplomatic hub.

Not Attacking Is Also an Action

Immune tolerance is not only a biological concept but also a mental metaphor. If even a single cell must learn to distinguish between "self" and "other," perhaps the human mind seeks a similar balance. Overprotection leads to autoimmunity in the body and polarization in society. Treg cells remind us that true power lies not in attacking, but in establishing balance.

Immune tolerance isn't passive surrender; it's a complex strategy. Thanks to Treg cells, the body both defends itself and prevents harm. As science advances, we better understand this intricate architecture of the immune system, and thanks to this, we realize that "tolerance" is a biological wisdom, even in human interactions. Perhaps our immune system is silently teaching us this: being truly strong doesn't come from winning every battle, but from knowing sometimes not to fight . So, where can you learn to tolerate instead of attack?

References and Suggested Readings

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Contreras-Castillo E. Stability and plasticity of regulatory T cells in health and disease . Journal of Leukocyte Biology.

Ge J. Regulatory T cells: masterminds of immune balance and future therapeutic innovations . Frontiers in Immunology. 2024.

Honing DY, Luiten RM, Matos TR. Regulatory T Cell Dysfunction in Autoimmune Diseases . International Journal of Molecular Sciences.

Josefowicz, S.Z., Lu, L.F., & Rudensky, A.Y. (2012). Regulatory T cells: Mechanisms of differentiation and function . Annual Review of Immunology, 30, 531–564.

Kümmel J. Opportunities and challenges harnessing antigen-specific Tregs / CAR-Tregs for IBD . Frontiers in Immunology, 2025.

Laukova M. Regulatory T cells as a therapeutic approach for... European Journal of Immunology (2023).

Lee, J. H., & Chi, H. (2025). The metabolic regulation of Treg cells in health and disease . Cell Metabolism, 37(1), 45–61.

Li Y. Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review . Journal of Translational Medicine. 2024.

Pan Y. Regulatory T cells in solid tumor immunotherapy . Cell & Cancer Reviews (2024/2025).

Park, J., Kim, Y. G., & Lee, S. H. (2024). Microbiota-derived signals shaping regulatory T cell function . Science Immunology, 9(84), eadi8824.

Sakaguchi, S., Mikami, N., Wing, J. B., Tanaka, A., Ichiyama, K., & Ohkura, N. (2020).

Regulatory T cells and human disease . Annual Review of Immunology, 38, 541–566.

Sharma, A., & Yadav, M. (2024). Revisiting immune tolerance: Regulatory T cells in autoimmunity and cancer . Nature Reviews Immunology, 24(3), 145–162.

Sumida TS et al. The regulation and differentiation of regulatory T cells and ... Review. 2024.

Vignali, D.A.A., Collison, L.W., & Workman, C.J. (2008). How regulatory T cells work . Nature Reviews Immunology, 8(7), 523–532.